Graduate student Weill Cornell Medicine Graduate School of Medical Sciences New York City, New York, United States
Disclosure(s):
Purnima Ravisankar, MS: No financial relationships to disclose
Introduction/Rationale: Gut microbiota and derived metabolites are crucial for priming and maturation of postnatal intestinal immune responses and homeostasis. Our recent study shows age-dependent variations in the gut metabolome, including enrichment of the neurotransmitter γ-aminobutyric acid (GABA) in neonate. This coincides with the key "window of opportunity" for microbiota-driven immune programming. However, the regulation and immunomodulatory role of neonatal gut GABA remain unknown. My proposal aims to elucidate the role of GABA in regulating intestinal immune under homeostasis and in response to microbial colonization in the neonatal gut.
Methods: GABA quantification by mass spectrometry in intestinal tissue and luminal contents of pathogen-free(SPF) and germ-free(GF) mice. Oral gavage of GABA or vehicle (PBS) in neonates, followed by flow cytometry analysis of lamina propria (LP) immune cells. GABA-gavaged GF neonates were used to study its role in regulating immune response to microbial colonization. Mice with GABAA receptor ablation in CD4+ T cells(Gabrb3 cKO) were used to probe signaling specificity. Enteric Citrobacter rodentium infection was used to investigate how GABA affects neonatal gut immunity.
Results: GABA in the neonatal small intestine is mainly derived from the gut microbiome. In the SI LP of GABA-treated neonates, I observed increased numbers of T cells producing inflammatory cytokines IFNg and IL-17A, compared to vehicle-treated neonates. GABA-gavaged neonatal GF mice showed significant increases in antigen-presenting cells, neutrophils, and effector CD4+ T helper 17 (Th17) cells post-conventionalization. The SI LP of Gabrb3 cKO mice had a significant increase in Th17 cells, compared to littermate controls. GABA gavage in SPF neonates conferred enhanced immunity against C. rodentium infection.
Conclusion: My findings demonstrate that microbiome-derived GABA promotes Th17 responses to microbial colonization, and confers protection against bacterial pathogens during postnatal development.
